This application is for continued support of a Program Project Grant in an NICHD-funded Mental Retardation Research Center (MRRC). The program, whose goal is to better understand the biochemical defects and pathogenesis of inborn errors that cause mental retardation, developmental disabilities, or other forms of central nervous system dysfunction, or early death, comprises five projects bound by focus, orientation, and research techniques. Disorders to be studied are glutaric acidemia type I, glutaric acidemia type II, defects of mitochondrial iron transport and storage, cystathionine beta-synthase (CBS) deficiency, and propionic acidemia. The investigators, Drs. Goodman, Kraus, Frerman and Koeller, have contiguous laboratories in the MRRC; share interests, methods, and equipment, and interact informally and in seminars and journal clubs on a daily basis. The first project will investigate Dr. Koeller's biochemical and molecular aspects of glutaric acidemia type 1 (GA1) and D-2-hydroxy-glutaric acidemia, both of which cause severe damage to the central nervous system in early life, and will seek to create a murine model of GA1. Dr. Koeller's project will investigate biochemical and molecular aspects of iron transport and storage in human mitochondria, disturbances of which cause Friedreich's ataxia and X-linked sideroblastic anemia and ataxia. One of Dr. Kraus' projects will examine biochemical and molecular aspects of electron flavoprotein-ubiquinone oxidoreductase (ETF-QO), the inner mitochondrial membrane protein whose deficiency is a cause of glutaric acidemia. The other project will study several aspects of CBS structure, function, and tissue distribution, including transcriptional and post-transcriptional regulation, and will examine an available murine model of CBS deficiency. The last project will extend investigations on the structure, function and regulation of the propionyl-CoA carboxylase A and B genes, and on the structure and function of the enzyme itself. The thread that unites these projects is the attempt to better understand the role these enzymes and pathways play in different tissues, how the enzyme defects cause disease, and how the diseases can be treated in a more rational manner.